SOD1 integrates signals from oxygen and glucose to repress respiration.
Cu/Zn superoxide dismutase (SOD1) is an abundant enzyme that has been best studied as a regulator of antioxidant defense. Using the yeast Saccharomyces cerevisiae, we report that SOD1 transmits signals from oxygen and glucose to repress respiration. The mechanism involves SOD1-mediated stabilization of two casein kinase 1-gamma (CK1γ) homologs, Yck1p and Yck2p, required for respiratory repression. SOD1 binds a C-terminal degron we identified in Yck1p/Yck2p and promotes kinase stability by catalyzing superoxide conversion to peroxide. The effects of SOD1 on CK1γ stability are also observed with mammalian SOD1 and CK1γ and in a human cell line. Therefore, in a single circuit, oxygen, glucose, and reactive oxygen can repress respiration through SOD1/CK1γ signaling. Our data therefore may provide mechanistic insight into how rapidly proliferating cells and many cancers accomplish glucose-mediated repression of respiration in favor of aerobic glycolysis.